首页|TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons

TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons

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Trimethylation of histone H3lysine 9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development. H3K9me3 also provides an essential mechanism for silencing transposable elements. However, previous studies have shown that canonical H3K9me3 readers (for example, HP1 (refs. 5-9) and MPP8 (refs. 10-12)) have limited roles in silencing endogenous retroviruses (ERVs), one of the main transposable element classes in the mammalian genome. Here we report that trinucleotide-repeat-containing 18 (TNRC18), a poorly understood chromatin regulator, recognizes H3K9me3 to mediate the silencing of ERV class Ⅰ (ERV1) elements such as LTR12 (ref. 14). Biochemical, biophysical and structural studies identified the carboxy-terminal bromo-adjacent homology (BAH) domain of TNRC18 (TNRC18(BAH)) as an H3K9me3-specific reader. Moreover, the amino-terminal segment of TNRC18 is a platform for the direct recruitment of co-repressors such as HDAC-Sin3-NCoR complexes, thus enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18(BAH)-mediated H3K9me3 engagement caused neonatal death in mice and, in multiple mammalian cell models, led to derepressed expression of ERVs, which affected the landscape of cis-regulatory elements and, therefore, gene-expression programmes. Collectively, we describe a new H3K9me3-sensing and regulatory pathway that operates to epigenetically silence evolutionary young ERVs and exert substantial effects on host genome integrity, transcriptomic regulation, immunity and development.

Shuai Zhao、Jiuwei Lu、Bo Pan、Huitao Fan、Stephanie D. Byrum、Chenxi Xu、Arum Kim、Yiran Guo、Krishna L. Kanchi、Weida Gong、Tongyu Sun、Aaron J. Storey、Nathaniel T. Burkholder、Samuel G. Mackintosh、Peyton C. Kuhlers、Ricky D. Edmondson、Brian D. Strahl、Yarui Diao、Alan J. Tackett、Jesse R. Raab、Ling Cai、Jikui Song、Gang Greg Wang

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Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA, Department of Pathology, Duke University School of Medicine, Durham, NC, USA, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

Department of Biochemistry, University of California, Riverside, CA, USA

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA, The First Affiliated Hospital of Harbin Medical University, Harbin, P. R. China

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA

Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA, Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA, Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA, Department of Pathology, Duke University School of Medicine, Durham, NC, USA, Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA, Department of Pathology, Duke University School of Medicine, Durham, NC, USA, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

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2023

10.1038/s41586-023-06688-z

Nature

Nature

ISSN：0028-0836
年,卷(期)：2023.623(7987)
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